The role of ERBB signaling in ibrutinib-resistant mantle cell lymphoma

Mantle cell lymphoma (MCL) is an incurable disease with frequent relapses despite high initial remission rates. MCL primarily originates from naïve B-cells that harbor the hallmark t(11;14)(q13;q32) chromosomal translocation leading to overexpression of the cell cycle regulatory protein cyclin D1. B-cell receptor (BCR) signaling is an oncogenic driver in mantle cell lymphoma (MCL). Inhibiting the BCR-downstream Bruton’s tyrosine kinase (BTK), using the drug ibrutinib, has proven to be a successful treatment although its effectiveness is only temporary. The causes of resistance to ibrutinib are not completely understood. Patients who initially respond to ibrutinib, but later experience relapse, face a grimmer outlook, emphasizing the need to understand resistance mechanisms for better treatment options. Through analysis of gene expression from MCL patients treated with ibrutinib, we have discovered several potential mechanisms that may enable MCL to evade the selective inhibition of BTK. Among these, increased expression of the plasma-cell biomarker syndecan-1 (SDC1/CD138) and erb-b2 receptor tyrosine kinase 4 (ERBB4) are particularly prominent in ibrutinib-resistant cases. We generated isogenic MCL cell-line models of ibrutinib resistance and independently demonstrated the critical role of ERBB signaling as observed in clinical samples. Importantly, simultaneous inhibition of these newly identified drug-resistance pathways with FDA-approved drugs, afatinib (targeting ERBB) and trametinib (targeting MEK), demonstrated significant and synergistic cytotoxicity against MCL cells resistant to ibrutinib. These initial findings provided the basis for our central hypothesis that MCL tumors can overcome BTK dependence by shifting towards survival mechanisms mediated through ERBB signaling. The objectives of this proposal are to elucidate the mechanisms driving resistance to BTK inhibition and to identify potential therapeutic targets that could effectively treat refractory and relapsed MCL. We will test the hypothesis by accomplishing the following specific aims: SA1, determine the role of ERBB signaling in ibrutinib-resistant (IR) MCL; and SA2, determine the efficacy of combination therapy using approved drugs such as afatinib and trametinib to treat IR MCL in vitro and in vivo using MCL patient-derived xenografts (PDXs). In vivo studies in immunodeficient mice are necessary to assess efficacy, pharmacodynamics of target engagement, and tolerability of drug combination in MCL PDX tumors within a physiologically relevant microenvironment, which cannot be adequately modeled in vitro or ex vivo alone. Our study proposal will have a two-fold impact on cancer research and patient outcomes. By understanding how a specific cancer can find ways to escape treatment, we can change the way we approach cancer research. We will not just focus on one target; we will also watch out for other potential ways the cancer might resist treatment. This understanding of how resistance works can also benefit patients because we can predict which treatments might work best based on their genetics and the likelihood of the cancer coming back. This way, we can tailor treatments to each patient and increase their chance of beating cancer. Project Number: 1R21CA296465-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: VU NGO | Institution: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE, DUARTE, CA | Award Amount: $457,683 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CTH-X (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11369418